Discovery of non-oxime reactivators using an in silico pharmacophore model of reactivators for DFP-inhibited acetylcholinesterase

• A rational strategy for discovery of 12 new DFP- inhibited non-oxime reactivators.
• An in silico pharmacophore model was used for the discovery.
• In vitro rate constant (kr) values were within ten-fold of pralidoxime (2-PAM).
• One compound showed in vivo efficacy comparable to 2-PAM against brain symptoms in guinea pigs.
• Reactivation by these non-oximes was never reported before to any OP-inhibited AChE.

Utilizing our previously reported in silico pharmacophore model for reactivation efficacy of oximes, we present here a discovery of twelve new non-oxime reactivators of diisopropylfluorophosphate (DFP)-inhibited acetylcholinesterase (AChE) obtained through virtual screening of an in-house compound database. Rate constant (kr) efficacy values of the non-oximes were found to be within ten-fold of pralidoxime (2-PAM) in an in vitro DFP inhibited eel AChE assay and one of them showed in vivo efficacy comparable to 2-PAM against brain symptoms for DFP induced neuropathology in guinea pigs. Short listing of the identified compounds were performed on the basis of in silico evaluations for favorable blood brain barrier penetrability, octanol–water partition (Clog P), toxicity (rat oral LD50) and binding affinity to the active site of the crystal structure of a OP- inhibited AChE.

Virtual screening of WRAIR-CIS database with the generated in silico pharmacophore model led us to identify 12 non-oxime reactivators against DFP-inhibited AChE showing efficacy within 10-fold of 2-PAM, one of which showed in vivo efficacy comparable to 2-PAM against brain symptoms for DFP-induced neuropathology in guinea pigs.Figure optionsDownload as PowerPoint slide